Dosage regimen of paliperidone palmitate extended-release injectable suspension

ABSTRACT

Provided herein are simplified dosing regimens for administering paliperidone palmitate to a patient in need of treatment of schizophrenia or schizoaffective disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. patentapplication Ser. No. 16/759,287, filed Apr. 24, 2020, which is a U.S.National Stage Patent Application of International Application No.PCT/US2018/057858, filed Oct. 26, 2018, which claims the benefit of U.S.Provisional Patent Application No. 62/578,082, filed Oct. 27, 2017, andU.S. Provisional Patent Application No. 62/647,333, filed Mar. 23, 2018,which applications are incorporated herein in their entireties.

BACKGROUND Technical Field

This disclosure relates to methods of treating psychosis or otherpsychiatric disorders with extended release paliperidone palmitateinjectable suspension.

Description of the Related Art

Paliperidone palmitate is used for the treatment of schizophrenia aloneor used in schizoaffective disorders as an adjunctive therapy toantidepressants. It is presently available in an extended release oraltablet (INVEGA® by Jansen Pharmaceuticals) or long acting extendedrelease aqueous injectable suspension suitable for intramuscular (IM)administration (INVEGA SUSTENNA® by Jansen Pharmaceuticals). Theintramuscular product has been approved and marketed in the U.S. since2006.

Paliperidone palmitate undergoes hydrolysis to yield paliperidone, themajor active metabolite of risperidone. The injectable formulation isfor intramuscular use and has been clinically demonstrated to be safe,well tolerated and with a high efficacy. Its prolonged release andduration of action are attributed to its slow dissolution rate andsubsequent hydrolysis to paliperidone.

Given its unique dissolution profile, current paliperidone palmitatetherapy requires that two initial loading doses be given one week apart,followed by regular monthly maintenance doses. See, e.g., U.S. Pat. No.9,439,906. In particular, INVEGA SUSTENNA® has five strengths at, indescending order, 234 mg, 156 mg, 117 mg, 78 mg and 39 mg ofpaliperidone palmitate, which are equivalents of 150 mg, 100 mg, 75 mg,50 mg and 25 mg of paliperidone, respectively. According to its label,INVEGA SUSTENNA® is intended to be administered at its highest strengthof 234 mg (i.e., 150 mg paliperidone) on day 1 followed by a secondloading dose of 156 mg (i.e., 100 mg paliperidone) on day 8. Thereafter,a monthly maintenance dose of 117 mg (i.e., 75 mg paliperidone) isrecommended. It is believed that after the initial two loading doses,serum concentration of the active metabolite can rapidly reachtherapeutic level and approach the steady-state concentration, which canbe further maintained by subsequent monthly maintenance doses. Themaintenance dosages may vary from 39 to 234 mg (i.e., 25 mg-150 mgpaliperidone) per month depending on tolerability and efficacy withrespect to the individual patient. The standard INVEGA SUSTENNA®regimens are referred to herein as “RLD regimens.”

Paliperidone palmitate therapy such as INVEGA SUSTENNA® requires twoloading doses one week apart in order to rapidly attain therapeuticplasma concentrations. Despite being long-acting in the maintenanceperiod, current therapy compels patient compliance at the initial dosingstage when the patient is the least capable. There exists a need in theart for improved dosage regimen in administering long-actingpaliperidone palmitate injectable suspension.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 shows the preliminary pharmacokinetic (PK) modeling andsimulation of a single, heightened loading dose followed by amaintenance dose according to an embodiment.

FIG. 2 demonstrates that the PK profiles according an embodiment of thepresent disclose as compared to the dosage regimen (RLD regimen)according to the label for INVEGA SUSTENNA®.

FIG. 3 demonstrates that the PK profiles of longer treatment into themaintenance period according to the dosing regimens disclosed herein andas compared to INVEGA SUSTENNA® regimen.

FIG. 4 shows the in vitro release profile of the drug product describedin Example 1 as compared to that of INVEGA SUSTENNA®.

FIG. 5 shows the respective mean plasma concentration-time profiles ofpaliperidone after a single IM injection of Example 1 and INVEGASUSTENNA®.

FIG. 6 demonstrates the PK profiles of the simplified dosing regimenhaving a heightened initial loading dose followed by monthly maintenancedoses according to an embodiment.

FIGS. 7A-7D show the PK curves of plasma concentration data obtainedfrom animal studies under RLD Regimen.

FIGS. 8A-8B shows the PK curves of plasma concentration data obtainedfrom animal studies under a dosing regimen according to an embodiment.

FIG. 9A-9D show the PK curves of plasma concentration data obtained fromanimal studies under a dosing regimen according to another embodiment.

FIG. 10A shows the average PK curves based on plasma concentration dataobtained from animal studies in different dosing regimens.

FIG. 10B shows the average PK curves based on plasma concentration dataobtained from studies in different dosing regimens.

BRIEF SUMMARY

Various embodiments provide dosing regimens having alternative initialloading doses, which dosing regimens address the drawbacks of thecurrently available therapy such as INVEGA SUSTENNA® while achieving acomparable level of systemic exposure during and following the initialdosing phrase. The represent disclosure demonstrates by pharmacokineticresults that it is feasible to achieve comparable systemic exposure byalternative dosing regimens. As such, some of the initial dosingregimens may be able to improve the patient convenience and, hence,increase compliance.

One embodiment provides a dosing regimen having a single, heightenedinitial loading dose followed by monthly maintenance doses. Thissimplified dosing regimen obviates two loading doses at the initialdosing stage, thereby enhancing patient compliance without compromisingtherapeutic effect. More specifically, it is provided a dosing regimenfor administering paliperidone palmitate to a patient in need oftreatment of schizophrenia or schizoaffective disorders, the dosingregimen comprising:

(1) administering intramuscularly to the patient a first loading dose of200 mg-300 mg of paliperidone as paliperidone palmitate on the first dayof treatment;

(2) beginning on the 29th day ±7 days from the first loading dose,administering intramuscularly to the patient monthly maintenance dose inthe range of 25 mg-150 mg of paliperidone as paliperidone palmitate,

wherein paliperidone palmitate is formulated in an aqueous suspensionformulation.

In more specific embodiments, the first loading dose comprises 225 mg ofpaliperidone as paliperidone palmitate.

In preferred embodiment, the first monthly maintenance dose is in therange of 50 mg-150 mg, or more preferably, 100 mg of paliperidone aspaliperidone palmitate. Thereafter, the maintenance doses may be in therange of 25 mg-150 mg paliperidone as paliperidone palmitate, dependingon tolerability and efficacy of the therapy for individual patient.

A further embodiment provides yet another dosing regimen foradministering paliperidone palmitate to a patient in need of treatmentof schizophrenia or schizoaffective disorders, the dosing regimencomprising:

(1) administering intramuscularly to the patient a first loading dose of150 mg-225 mg of paliperidone as paliperidone palmitate on the first dayof treatment;

(2) administering intramuscularly to the patient a second loading doseof 50 mg-100 mg of paliperidone as paliperidone palmitate on the 15thday ±3 days from the first day of treatment;

(3) beginning on the 36th day ±7 days from the first loading dose,administering intramuscularly to the patient monthly maintenance dose of25 mg-150 mg of paliperidone as paliperidone palmitate, whereinpaliperidone palmitate is formulated in an aqueous suspensionformulation.

In more specific embodiments, the first loading dose comprises 200 mg ofpaliperidone as paliperidone palmitate.

In a preferred embodiment, the second loading dose is 50 mg ofpaliperidone as paliperidone palmitate. In other embodiments, the firstmonthly maintenance does is 75 mg. Thereafter, the maintenance doses maybe in the range of 25 mg-150 mg (e.g., 75 mg) paliperidone aspaliperidone palmitate, depending on tolerability and efficacy ofindividual patient.

DETAILED DESCRIPTION Paliperidone Palmitate Injectable Suspension

The active ingredient of the intramuscular (IM) injectable suspension ispaliperidone palmitate. Paliperidone palmitate is the palmitate ester ofpaliperidone, the major active metabolite of risperidone. The chemicalname is (9RS)-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimadin-9-ylhexadecanoate. The manufacturing process of paliperidone palmitatecomprises a single synthetic step of esterification of paliperidone withpalmitic acid, followed by a sterilization process.

Paliperidone palmitate is practically insoluble in aqueous media over abroad pH range. This low solubility allows the drug substance to beformulated as an aqueous suspension for IM injection, which provides anextended release profile that is a function of drug substance particlesize.

Paliperidone palmitate can be micronized to desired sizes, which aregenerally less than 100 microns, or more typically less than 10 microns,including submicron ranges (i.e., nanometer ranges). The particle sizescan impact the dissolution of paliperidone palmitate, which in turn canimpact the release rate of the active metabolite. Typically, largerparticles are slower to dissolve and therefore slower to release theactive metabolite. Micronization of paliperidone palmitate can becarried out by methods known in the art, including those disclosed inU.S. Pat. No. 9,439,906.

The paliperidone palmitate particle sizes can be characterized by sizedistribution within a sample. In certain embodiments, 90% of theparticles are less than 100 μm in diameters (e.g., d(0.9) is 100 μm). Inother embodiments, 90% of the particles are less than 10 μm (e.g.,d(0.9) is 10 μm). In other embodiments, 90% of the particles are lessthan 5 μm (e.g., d(0.9) is 5 μm). In certain embodiments, the massmedian diameter (d(0.5)), i.e., the size where 50% of the particles areabove and 50% of the particles are below, is in the range of 100 nm-2μm. In further embodiments, the mass median diameter is in the range of500 nm-1.6 μm. In further embodiments, the mass median diameter is about900 nm-1.2 μm.

Particle sizes of paliperidone palmitate may also be characterized byspecific surface area (SSA). As used herein, the particle sizes ofpaliperidone palmitate may be in the range of 2-15 m²/g. In certainembodiments, the particle sizes are in the range of 5-11 m²/g. In otherembodiments, the particle sizes are in the range of 2-8 m²/g, or in therange of 7-10 m²/g, or in the range of 10-12 m²/g, or in the range of10-15 m²/g.

Paliperidone palmitate can be formulated as a suspension in anypharmaceutically acceptable diluent including, for example, water. Thesuspension may further include one or more additives such as buffer,isotonizing agent, preservatives, surfactants, wetting agents suspendingagents, and the like.

Suitable suspending agents for use in the aqueous suspensions accordingto the present invention are cellulose derivatives, e.g. methylcellulose, sodium carboxymethyl cellulose and hydroxypropyl methylcellulose, polyvinylpyrrolidone, alginates, chitosan, dextrans, gelatin,polyethylene glycols, polyoxyethylene- and polyoxypropylene ethers.Preferably sodium carboxymethyl cellulose is used in a concentration of0.5 to 2%, most preferably 1% (w/v).

Suitable wetting agents for use in the aqueous suspensions according tothe present invention are polyoxyethylene derivatives of sorbitanesters, e.g. polysorbate 20 and polysorbate 80, lecithin,polyoxyethylene- and polyoxypropylene ethers, sodium deoxycholate.Preferably polysorbate 20 is used in a concentration of 0.5 to 3%, morepreferably 0.5 to 2%, most preferably 1.1% (w/v).

Suitable buffering agents are salt of weak acids and should be used inamount sufficient to render the dispersion neutral to very slightlybasic (pH is 7.0-8.5), preferably in the pH range of 7 to 7.5.Particularly preferred is the use of a mixture of disodium hydrogenphosphate (anhydrous) (typically about 0.9% (w/v)) and sodium dihydrogenphosphate monohydrate (typically about 0.6% (w/v)). This buffer alsorenders the dispersion isotonic and, in addition, less prone toflocculation of the ester suspended therein.

Preservatives are antimicrobials and anti-oxidants which can be selectedfrom the group consisting of benzoic acid, benzyl alcohol, butylatedhydroxyanisole, butylated hydroxytoluene, chlorbutol, a gallate, ahydroxybenzoate, EDTA, phenol, chlorocresol, metacresol, benzethoniumchloride, myristyl-gamma-piccolinium chloride, phenylmercuric acetateand thimerosal. In particular, it is benzyl alcohol which can be used ina concentration up to 2% (w/v), preferably up to 1.5% (w/v).

Isotonizing agents are, for example, sodium chloride, dextrose,mannitol, sorbitol, lactose, sodium sulfate. The suspensionsconveniently comprise from 0 to 10% (w/v) isotonizing agent. Mannitolmay be used in a concentration from 0 to 7% More preferably, however,from about 1 to about 3% (w/v), especially from about 1.5 to about 2%(w/v) of one or more electrolytes are used to render the suspensionisotonic, apparently because ions help to prevent flocculation of thesuspended ester. In particular, electrolytes of the buffer serve asisotonizing agent.

Additional detailed description of the preparation of paliperidonepalmitate suspension may be found in U.S. Pat. Nos. 6,555,544,9,439,906, which are incorporated herein by reference in theirentireties.

In various embodiments, the aqueous suspension formulations maycomprise, by the weight percentage based on the total weight of theformulation: (a) from 3 to 20% (w/w) of paliperidone palmitate; (b) from0.5 to 2% (w/w) of a wetting agent; (c) one or more buffering agentssufficient to render the composition neutral to very slightly basic (pH8.5); (d) from 0.5 to 4% (w/w) of a suspending agent; (e) up to 2% (w/w)preservatives; and (f) water q.s. ad 100%. Preferably the aqueoussuspension will be made under sterile conditions and no preservativeswill be used.

In preferred embodiments, the aqueous suspension formulation is anaqueous suspension of particulate paliperidone palmitate having the sizedistribution as disclosed herein. Suitable additives include polysorbate20, polyethylene glycol 4000, citric acid monohydrate, disodium hydrogenphosphate anhydrous, sodium dihydrogen phosphate monohydrate, sodiumhydroxide. The amount of paliperidone palmitate in the aqueoussuspension formulation may be: 39 mg, 78 mg, 117 mg, 156 mg, 234 mg, 312mg, 351 mg, 390 mg and 468 mg, which correspond to 25 mg, 50 mg, 75 mg,100 mg, 150 mg, 200 mg, 225 mg, 250 mg and 300 mg of paliperidone,respectively. In various embodiments, the concentration of paliperidonepalmitate in aqueous suspension formulation is about 15 w/w %.

Dosage Regimen

Based on the collective comparable in vitro dissolution data, thepreclinical animal PK data and the preliminary pharmacokinetic (PK)modeling and simulation using available human PK data of INVEGASUSTENNA®, provided herein are alternative dosing regimens havingsimplified initial dosing phases while achieving a superior orcomparable level of systemic exposure of paliperidone to that of theinitial dosing regimen of INVEGA SUSTENNA®. Advantageously, the dosingregimens are capable of enhancing patient compliance, especially duringthe initial dosing phase when patient compliance is critical inachieving adequate efficacy that may induce future compliance during themaintenance period.

Thus, one embodiment provides a dosing regimen having a single,heightened initial loading dose followed by monthly maintenance doses.This simplified dosing regimen obviates two loading doses at the initialdosing stage, thereby enhancing patient compliance without compromisingtherapeutic effect. More specifically, provided is a dosing regimen foradministering paliperidone palmitate to a patient in need of treatmentof schizophrenia or schizoaffective disorders, the dosing regimencomprising:

(1) administering intramuscularly to the patient a first loading dose of200 mg-300 mg of paliperidone as paliperidone palmitate on the first dayof treatment;

(2) beginning on the 29th day ±7 days from the first loading dose,administering intramuscularly to the patient monthly maintenance dose inthe range of 25 mg-150 mg-of paliperidone as paliperidone palmitate,wherein paliperidone palmitate is formulated in an aqueous suspensionformulation.

In a preferred embodiment, the first loading dose comprises 225 mg ofpaliperidone as paliperidone palmitate.

As used herein, a “loading dose” is a heightened dose typically given atthe beginning of a course of treatment. The first loading dose is givenon the first day (day 1) of the treatment and is at a higher amount thanany of the doses given thereafter. Loading dose is typically followed bymaintenance doses given at regular intervals, although sometimes asecond loading dose may be given after the first loading dose and beforethe maintenance doses.

As used herein, “monthly maintenance dose” refers to regularlyadministered injection within about four weeks (28 days ±7 days) fromthe immediate preceding dose. The immediate preceding dose may be theinitial loading dose. Thus, according to this embodiment, the firstmonthly maintenance dose begins on the 29th day (or within a window of±7 days thereof) from the initial loading dose on day 1. The secondmonthly maintenance dose begins on the 29th day (within a window of ±7days thereof) from the immediate preceding dose (e.g., the first monthlymaintenance dose), and so forth.

During the maintenance period in which regular monthly injections aregiven, each dosing strength may be the same or different. In a preferredembodiment, the first monthly maintenance dose is in the range of 50-150mg paliperidone as paliperidone palmitate, or more specifically, 100 mgof paliperidone as paliperidone palmitate. Thereafter, the one or morefurther monthly maintenance doses may be in the range of 25 mg-150 mgpaliperidone as paliperidone palmitate, depending on tolerability andefficacy of the therapy on individual patient. Specifically, the monthlymaintenance doses may be 150 mg, 100 mg, 75 mg, 50 mg, or 25 mg ofpaliperidone as paliperidone palmitate. In a preferred embodiment, thefurther monthly maintenance doses are 75 mg of paliperidone aspaliperidone palmitate.

FIG. 1 shows the preliminary pharmacokinetic modeling and simulation. Asshown, a single, heightened loading dose of 225 mg is followed by amaintenance dose in different strengths within 28 days (i.e., given onthe 29th day from the loading dose administered on the first day). ThePK profiles closely track the PK profile of INVEGA SUSTENNA® dosingregimen according to its label (i.e., the “RLD” regimen), indicatingthat a sufficiently high therapeutic level of the active substance isachieved under the simplified regimen having a single loading dose.

A further embodiment provides yet another dosing regimen by which twoinitial loading doses are administered about two weeks (14 days) apart,followed by monthly maintenance doses. More specifically, it is provideda dosing regimen for administering paliperidone palmitate to a patientin need of treatment of schizophrenia or schizoaffective disorders, thedosing regimen comprising:

(1) administering intramuscularly to the patient a first loading dose of150 mg-225 mg of paliperidone as paliperidone palmitate on the first dayof treatment;

(2) administering intramuscularly to the patient a second loading dosein the range of 50-100 mg of paliperidone as paliperidone palmitate onthe 15th day ±3 days from the first day of treatment;

(3) beginning on the 36th day ±7 days from the first loading dose,administering intramuscularly to the patient monthly maintenance dose of25 mg-150 mg of paliperidone as paliperidone palmitate formulated in anaqueous suspension formulation.

In preferred embodiments, the second loading dose is 50 mg paliperidoneas paliperidone palmitate. In other embodiments, the first monthlymaintenance dose is 75 mg of paliperidone as paliperidone palmitate.Thereafter, the one or more further monthly maintenance doses may be inthe range of 25 mg-150 mg paliperidone as paliperidone palmitate,depending on tolerability and efficacy of the therapy on the individualpatient. Specifically, the monthly maintenance doses may be 150 mg, 100mg, 75 mg, 50 mg, or 25 mg of paliperidone as paliperidone palmitate.

FIG. 2 demonstrates that, in simulation, the PK profiles according tothe above embodiment track closely to that of INVEGA SUSTENNA® (shown ashaving an initial loading dose of 150 mg on day 1).

FIG. 3 demonstrates that, in simulation, the PK profiles of longertreatment into the maintenance period according to the dosing regimensdisclosed herein also track closely to the conventional therapy, furtherindicating the efficacy of the improved dosing regimens.

Treatment of Psychosis or Psychiatric Disorders

The therapy disclosed herein is suitable for treating or alleviating thesymptoms of psychosis and psychiatric disorders in patients for all theknown uses of risperidone. These mental disorders include, but are notlimited to, schizophrenia; bipolar disorder or other disease states inwhich psychosis, aggressive behavior, anxiety or depression isevidenced. Schizophrenia refers to conditions characterized asschizophrenia, schizoaffective disorder and schizophreniform disorders,in DSM-IV-TR such as category 295.xx.

EXAMPLES Example 1 Drug Product

The injectable paliperidone palmitate describe herein is developed as awhite to off-white sterile aqueous extended-release suspension forintramuscular injection. Table 1 shows paliperidone palmitate injectablesuspension in various strengths. In addition to the active paliperidonepalmitate, other components are listed by their respective weight andw/w percentages. Other strengths, including 312 mg, 351 mg, 390 mg and468 mg of paliperidone palmitate, can be prepared by proportionallyadjusting the various ingredients in the formulations.

TABLE 1 Unit Formula (mg) 39 78 117 156 234 Percentage Compositions mgmg mg mg mg (w/w %) Paliperidone 39 78 117 156 234 15.04 palmitateCitric acid 1.25 2.50 3.75 5.00 7.50 0.48 monohydrate Disodium hydrogen1.25 2.50 3.75 5.00 7.50 0.48 phosphate anhydrous Sodium dihydrogen 0.621.25 1.88 2.50 3.75 0.24 phosphate monohydrate Sodium hydroxide 0.711.42 2.13 2.84 4.27 0.27 Polyethylene glycol 7.5 15.0 22.5 30.0 45.02.89 4000 Polysorbate 20 3 6 9 12 18 1.16 Water for Injection 206 412618 824 1236 79.43

Paliperidone palmitate is micronized aseptically using wet milling. Theaseptic wet milling process uses a type of milling beads in the millmachine to obtain particles of micronized paliperidone palmitate withdesired size distribution. In this process, the sterility of the finalproduct is ensured by using a sterilization filtration and asepticprocess. The injectable suspension is provided in a prefilled syringewith a plunger stopper and tip cap. The kit also contains 2 safetyneedles (a 1½-inch 22 gauge safety needle and a 1-inch 23 gauge safetyneedle). Table 2 shows that the particle size distributions in thepaliperidone palmitate injectable suspension are the same or comparableto those of the commercial INVEGA SUSTENNA®.

TABLE 2 Size distribution (μm) Samples d(0.1) d(0.5) d(0.9) Example 10.449 0.995 2.504 INVEGA SUSTENNA ® 0.497 1.067 2.598

The in vitro release of the injectable suspension is evaluated by theFDA recommended dissolution method for paliperidone palmitate extendedrelease suspension using USP Type II (paddle) apparatus with 900 mL0.001 M HCl containing 0.489% Polysorbate 20 at temperature 25±0.5° C.at 50 rpm. The results showed that the in vitro release profile ofExample 1 is identical to that of INVEGA SUSTENNA® (FIG. 4 ).

The paliperidone palmitate injectable suspension includes the followingstrengths: 39 mg, 78 mg, 117 mg, 156 mg, 234 mg, 312 mg, 351 mg, 390 mgand 468 mg which correspond to 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200mg, 225 mg, 250 mg and 300 mg of paliperidone, respectively.

Example 2 In Vivo Animal Study Based on a Single Dose

A pharmacokinetic study in Beagle dogs indicated that followingintramuscular administration, the plasma exposure of 3.1 mg/kg of theinjectable suspension of Example 1 (based on the paliperidone palmitate)was comparable to that of 3.1 mg/kg of INVEGA SUSTENNA®. In support ofthe rationale for the proposed development program, preclinical studiesin beagle dogs were performed. Beagle dogs were randomly divided in twogroups (five animals/group/sex). Group 1 received single IM injection ofExample 1 at 3.1 mg/kg, and Group 2 received single IM injection ofINVEGA SUSTENNA® at 3.1 mg/kg. Blood samples (1.0 mL) was collected atpre-dose and 1 h, 6 h, 1 d, 2 d, 4 d, 7 d, 9 d, 11 d, 14 d, 17 d, 21 d,24 d, 28 d, 31 d, 35 d post dose. Paliperidone was determined byLC-MS/MS method.

The mean plasma concentration-time profiles of paliperidone after asingle IM injection of Example 1 and INVEGA SUSTENNA® were shown in FIG.5 . Summary pharmacokinetic parameters are presented in Table 3.

TABLE 3 Pharmacokinetic parameters of paliperidone after a single IMinjection of Example 1 and INVEGA SUSTENNA ® in dogs (n = 10) ParametersT_(max) C_(max) F- C_(max) AUC_((0-t)) F-AUC_((0-t)) Unit Day μg/L %μg/L*d % Example 1 8.20 ± 3.55 73.01 ± 53.84 101.91 896.27 ± 460.43104.80 INVEGA 8.73 ± 4.78 71.64 ± 56.92 — 855.23 ± 382.01 — SUSTENNA ®

The relative bioavailability (AUC) of Example 1 in dogs was 104.80% andC_(max) was 101.91%, respectively, when compared to INVEGA SUSTENNA® atan equivalent i.m. dose of 3.1 mg/kg.

Example 3 Monthly Dosing Having High Initial Loading Dose—a SimulatedStudy

The simplified dosing regimen according on one embodiment comprises ahigh loading dose followed by monthly maintenance doses for the drugproduct of Example 1. The regimen requires one fewer dose initially andallows for a longer interval between the first loading dose and thesubsequent maintenance dose, when compared to the standard INVEGASUSTENNA® dosing regimen (RLD regimen). FIG. 6 demonstrates thesimulated PK profiles of the simplified dosing regimen disclosed hereinhaving a heightened initial loading dose following by monthlymaintenance doses compared to the simulated PK profile of the RLDregimen.

The clinical simulations show a faster onset of drug release and lessfluctuations in the plasma profiles over the first two months andcomparability thereafter. The following table summarizes the analysisincluding partial AUC breakdowns.

TABLE 4 Simplified Dosing Regimen with high RLD Regimen initial 150 mg(1d) + loading dose 100 mg(8 d) + 225 mg(1 d) + 1 75 mg(36 d) + 00 mg(29d) + 75 mg(64 d) + 75 mg(57 d) + Parameters 75 mg(92 d) 75 mg(85 d)Total Dose (mg) 475 475 T_(max) (day) 19 15 C_(max) (ng/mL) 23.83 22.05AUC_(1-15 d)(d*ng/mL) 192.04 228.64 F-AUC(%) — 119.06AUC_(1-31 d)(d*ng/mL) 540.89 537.86 F-AUC(%) — 99.44AUC_(1-61 d)(d*ng/mL) 1046.53 1085.38 F-AUC(%) — 103.71AUC_(last)(d*ng/mL) 2106.73 2098.17 F-AUC(%) — 99.59 F-C_(max)(%) —92.52

Example 4 Pharmacokinetic Studies of Dosing Regimens in Animal Testing

Animal testing was also carried out to analyze the in vivo PK behaviorsunder the various dosing regimens disclosed herein.

Test Animals

20 healthy male beagle dogs (average weight about 11 kg) were randomlydivided into 5 groups (Groups I-V) with 4 dogs in each group. Eachanimal was assigned its own number (#1-#20).

Dosing Regimens

Group I animals (#1-#4) and Group IV animals (#13-#16) were tested underRLD regimen. Group II animals (#5-#8) were tested under Regimen A. GroupIII animals (#9-#12) and Group V animals (#17-#20) were tested underRegimen B. Table 5 summarizes the respective human dosages (mg ofpaliperidone) and the equivalent animal dosages (converted to mg/kg) andthe dosing intervals under each dosing regimen.

TABLE 5 Dosing Regimens Day 1 Day 8 Day 15 Day 29 Day 36 RLD Human 150mg 100 mg 75 mg Group I 4.6 mg/kg 3.1 mg/kg 2.3 mg/kg Group IV 4.6 mg/kg3.1 mg/kg 2.3 mg/kg Regimen A Human 200 mg 50 mg 75 mg Group II 6.2mg/kg 1.5 mg/kg 2.3 mg/kg Regimen B Human 225 mg 100 mg Group III 6.9mg/kg 3.1 mg/kg Group V 6.9 mg/kg 3.1 mg/kg

Sample Collection

The animals in each group received intramuscular injections according tothe dosing regimen assigned to the group. Blood samples (1ml/collection) were collected from the forelimb vein of each beagleimmediate before administration (at 0 h), and thereafter at timeintervals of 6 h (day 1), 24 hr (day 2), day 3, day 5, day 8 (prior todosing for groups receiving RLD regimen), day 9, day 11, day 13, day 15(prior to dosing for groups receiving Regimen A), day 17, day 19, day22, day 24, day 26, day 29 (prior to dosing for groups receiving RegimenA), day 30, day 32, day 34, day 36 (prior to dosing for groups receivingRLD and Regimen A), day 37, day 39, day 42, day 45, day 47, day 50, day53, day 57, day 64, day 71, day 78, and day 85. The blood samples wereplaced in heparinized centrifuge tubes and centrifuged for 10 min (3500rpm). The plasma was separated, collected and stored under −80° C.

PK Data Under RLD Regimen

Plasma concentrations of the samples collected from Group I and Group IVanimals are shown in Table 6.

TABLE 6 Time Plasma Concentration (ng/ml) Plasma Concentration (ng/ml)(day) #1 #2 #3 #4 mean SD #13 #14 #15 #16 mean SD 1 0 0 0 0 0.00 0.00 00 0 0 0.00 0.00 1.25 2.87 5.52 2.79 2.43 3.40 1.42 10.7 9.29 7.59 7.228.70 1.61 2 14.2 15.6 9.97 12.6 13.09 2.42 24.8 32.1 22.3 17.7 24.236.02 3 23.1 16.7 13.1 25.6 19.63 5.74 26.7 43.1 38.3 18 31.53 11.34 520.4 20.1 14.4 34.7 22.40 8.65 25.3 42.8 54.9 11.1 33.53 19.27 8 35.740.1 21.1 65 40.48 18.26 31.95 91.5 98 11.7 58.29 42.99 9 42.5 79 39.9136.5 74.48 45.04 54 124.5 110 25.8 78.58 46.50 11 43.7 96.9 58.4 148.586.88 46.81 60.5 85 90.5 26.5 65.63 29.16 13 55.5 119.5 73 189 109.2559.63 68 116 132 21.75 84.44 49.86 15 85 155 96 195.5 132.88 51.84 130.598 148.5 20.6 99.40 56.54 17 91 78 85 185 109.75 50.45 130.5 113.5 12522.9 97.98 50.55 19 94.5 53 82.5 144.5 93.63 38.14 88.5 49.45 96 18.9563.23 35.88 22 132 35.75 93.5 150.5 102.94 50.70 56.5 45.5 71.6 24.549.53 19.82 24 146 25.65 89 115 93.91 51.13 45.5 38 43.1 23.5 37.53 9.8626 103 15.15 67.5 68.5 63.54 36.24 33 29.7 26.3 23.5 28.13 4.12 29 74.89.14 55.7 42.1 45.44 27.67 21.8 27.1 20.8 23.9 23.40 2.78 30 72 7.17 5030.5 39.92 27.64 21.5 25.1 16.3 22.6 21.38 3.70 32 52.6 4.52 45.5 17.630.06 22.76 16.7 24.9 13 18 18.15 4.97 34 40.5 3.1 37.7 13.1 23.60 18.3917 25 11 14.9 16.98 5.90 36 28.9 2.46 28.4 7.15 16.73 13.90 16.8 22.68.65 11.7 14.94 6.12 37 35.4 6.59 38.2 45.2 31.35 17.01 55.5 54.3 24.223.1 39.28 18.05 39 44 12.8 41.3 69.4 41.88 23.15 55.5 77.6 55.8 18.851.93 24.39 42 44.6 22.5 39.1 55.7 40.48 13.83 39.9 67.6 99 12.7 54.8037.02 45 47.7 30.8 45.2 45.9 42.40 7.80 31.1 64 61.7 12.9 42.43 24.75 4744.7 27.1 37 42 37.70 7.75 26.2 45 39.6 11.3 30.53 15.06 50 51.2 23.634.5 35.5 36.20 11.36 20.3 31.1 26.5 11.7 22.40 8.39 53 45.2 15.6 40.221.3 30.58 14.34 15 24.4 15 10.3 16.18 5.91 57 30.9 10.3 36 14.9 23.0312.36 11.9 18.1 6.95 9.96 11.73 4.71 64 14.9 3.41 30.3 4.78 13.35 12.417.9 12.6 2.1 10.5 8.28 4.54 71 10.8 0.5 23.8 3.3 9.60 10.42 4.35 8.721.08 7.42 5.39 3.41 78 5.88 0 20.6 1.72 7.05 9.36 2.23 5.21 0.5 6.243.55 2.65 85 3.86 0 15.5 0.5 4.97 7.23 1.38 4.11 0 4.6 2.52 2.20

The PK data shown in Table 6 are plotted into various PK curves. FIG. 7Ashows the PK curves of plasma concentration data obtained from Group Ianimals. FIG. 7B shows the PK curve based on the average plasmaconcentration data obtained from Group I animals.

FIG. 7C shows the PK curves based on the plasma concentration dataobtained from Group IV animals. Data from one animal (#16) appeared todeviate from its cohorts. FIG. 7D shows the respective PK curves basedon the average data of Group IV animals with or without taking intoconsideration of data from #16 animal.

Table 7 summarizes the PK parameters derived from the PK curves forGroups I and IV animals. Standard deviation (SD) and coefficient ofvariation (CV %) are also provided.

TABLE 7 T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) T_(max-1) C_(max-1)T_(max-2) C_(max-2) d μg/L μg/L*d μg/L*d d μg/L d μg/L Group #1 24.00146.00 3632.18 3682.95 24.00 146.00 50.00 51.20 I #2 15.00 155.002010.03 2012.83 15.00 155.00 45.00 30.80 #3 15.00 96.00 3477.47 4010.1415.00 96.00 45.00 45.20 #4 15.00 195.50 4210.47 4214.96 15.00 195.5039.00 69.40 Mean 17.25 148.13 3332.54 3480.22 17.25 148.13 44.75 49.15SD 4.50 40.88 936.41 1002.49 4.50 40.88 4.50 15.99 CV % 26.09 27.6028.10 28.81 26.09 27.60 10.06 32.52 Group #13 15.00 130.50 2528.692546.38 15.00 130.50 37.00 55.50 IV #14 9.00 124.50 3241.40 3312.15 9.00124.50 39.00 77.60 #15 15.00 148.50 3191.02 3194.15 15.00 148.50 42.0099.00 #16 11.00 26.50 1190.27 1311.82 11.00 26.50 — — Mean 12.50 107.502537.85 2591.12 12.50 107.50 39.33 77.37 SD 3.00 54.95 955.28 916.903.00 54.95 2.52 21.75 CV % 24.00 51.12 37.64 35.39 24.00 51.12 6.4028.11

PK Data Under Regimen A

Plasma concentrations of the samples collected from Group II animals areshown in Table 8.

TABLE 8 Time Concentration (ng/ml) (day) #5 #6 #7 #8 mean SD 1 0 0 0 00.00 0.00 1.25 6.39 5.57 2.28 5.37 4.90 1.80 2 27.5 15.4 14.6 21.2 19.685.99 3 44.8 20.7 21.8 28.6 28.98 11.11 5 55.5 30.6 22.9 35.2 36.05 13.928 75.6 70.6 72.2 50 67.10 11.59 9 92.5 92.5 83.5 60 82.13 15.35 11 92.589 88.5 54 81.00 18.09 13 72 75 89 47.65 70.91 17.19 15 56.5 54 79.540.75 57.69 16.10 17 81.5 60.5 100 29.1 67.78 30.42 19 104 40.1 68.527.15 59.94 34.08 22 125 40.05 73.5 31.75 67.58 42.32 24 116.5 31.65 6527.5 60.16 41.14 26 102 23.25 43.15 24.25 48.16 37.04 29 95.7 29.4 41.823.6 47.63 32.94 30 93.5 30.3 44.4 20.3 47.13 32.46 32 72 25.4 42.2 17.539.28 24.13 34 54.5 24 39.4 17.4 33.83 16.58 36 49.9 24.6 37.8 17.432.43 14.39 37 119.5 45.3 63.6 27.1 63.88 39.97 39 83.8 99.7 76.3 37.674.35 26.37 42 59.4 166 68.8 58.7 88.23 52.05 45 45.8 71.9 55 64.4 59.2811.34 47 32.6 49.8 43.9 46.6 43.23 7.48 50 25.5 31.5 33.2 29 29.80 3.3553 19.6 21.5 27.6 23.6 23.08 3.43 57 16.3 16.6 22.6 19.6 18.78 2.95 6411.9 12.1 13.8 14.4 13.05 1.24 71 9.25 10.1 9.1 13.1 10.39 1.86 78 7.148.63 6.89 10 8.17 1.44 85 7.21 7.98 4.89 9.48 7.39 1.91

The PK data shown in Table 8 are plotted into various PK curves. FIG. 8Ashows the PK curves of plasma concentration data obtained from Group IIanimals. FIG. 8B shows the PK curve based on the average plasmaconcentration data obtained from Group II animals.

Table 9 summarizes the PK parameters derived from the PK curves forGroup II animals. Standard deviation (SD) and coefficient of variation(CV %) are also provided.

TABLE 9 T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) T_(max-1) C_(max-1)T_(max-2) C_(max-2) d μg/L μg/L*d μg/L*d d μg/L d μg/L #5 22.00 125.004069.12 4285.47 22.00 125.00 37.00 119.50 #6 42.00 166.00 3146.753544.02 9.00 92.50 42.00 166.00 #7 17.00 100.00 3336.44 3446.66 17.00100.00 39.00 76.30 #8 45.00 64.40 2282.89 2612.80 9.00 60.00 45.00 64.40Mean 31.50 113.85 3208.80 3472.24 14.25 94.38 40.75 106.55 SD 14.0642.74 734.30 684.54 6.40 26.80 3.50 46.17 CV % 44.63 37.54 22.88 19.7144.89 28.40 8.59 43.33

PK Data Under Regimen B

Plasma concentrations of the samples collected from Group III and GroupV animals are shown in Table 10.

The PK data shown in Table 10 are plotted into various PK curves. FIG.9A shows the PK curves of Group III animal data. Data from one animal(#9) appeared to deviate from its cohorts. FIG. 9B shows the respectivePK curves based on the average data of Group III animals (with orwithout taking into consideration of data from #9 animal).

FIG. 9C shows the PK curves of Group V animal data. Data from one animal(#18) appeared to deviate from its cohorts. FIG. 9D shows the respectivePK curves based on the average data of Group V animals (with or withouttaking into consideration of data from #18 animal).

TABLE 10 Time Plasma Concentration (ng/ml) Plasma Concentration (ng/ml)(day) #9 #10 #11 #12 mean SD #17 #18 #19 #20 mean SD 1 0 0 0 0 0.00 0.000 0 0 0 0.00 0.00 1.25 2.36 3.61 7.12 1.34 3.61 2.52 15.8 6.85 9.08 19.512.81 5.86 2 4.26 14.1 40.2 7.03 16.40 16.40 52.1 15.3 24.8 51.2 35.8518.66 3 6.35 19.9 74.1 13.8 28.54 30.88 67.1 11.6 29 45.9 38.40 23.71 57.19 65.2 90.7 18 45.27 39.39 9. 12.8 24.6 32.3 40.68 35.79 8 9.3 161.5223 44.3 109.53 99.80 144 16.35 42.25 37.05 59.91 57.16 9 11.05 164.5252 64 122.89 107.05 222.5 21.45 55.5 42 85.36 92.49 11 14.95 112.5 212108 111.86 80.49 224.5 22.7 70 44.65 90.46 91.42 13 18.35 84.5 178 8390.96 65.71 198.5 24 55.5 64 85.50 77.27 15 21.15 75 161.5 85.5 85.7957.81 122 17.65 42.55 83.5 66.43 45.93 17 24.65 52 152.5 78.5 76.9154.98 118 21.2 35 105.5 69.93 48.89 19 19.7 38.7 101.5 51 52.73 34.9787.5 14.15 24.55 69 48.80 35.09 22 28.4 33.4 102.5 39.55 50.96 34.66 6015.7 19.9 80.9 44.13 31.62 24 24 25.1 91.5 35.25 43.96 32.09 51.8 13.621.5 68.8 38.93 25.84 26 23.2 17.8 55.5 30.35 31.71 16.67 40.4 10.7 18.251.8 30.28 19.10 29 26.1 14 36.4 28.1 26.15 9.25 33.7 9.8 15.3 61.530.08 23.31 30 29.7 17.1 23.1 27.9 24.45 5.64 59.2 27.9 28 73.6 47.1822.96 32 26.2 24.9 73 32.4 39.13 22.82 131 38.5 38.9 91.9 75.08 44.93 3422.4 32.9 81.4 32.6 42.33 26.50 172.5 40.6 42.6 96.5 88.05 61.97 36 18.952.7 89.9 38.7 50.05 29.97 154.5 41.1 50.7 84 82.58 51.35 37 19.9 58.376 37.6 47.95 24.41 131.5 38.2 46 86.3 75.50 42.87 39 21.9 55.7 74.742.9 48.80 22.19 129.5 35.2 41.6 111 79.33 47.93 42 21 51.1 72.3 38.145.63 21.64 84.3 22.2 41.1 97.6 61.30 35.51 45 19.2 30.9 64.7 32.4 36.8019.51 45.8 16.5 30.2 65.2 39.43 20.94 47 20.7 20.5 49.5 31 30.43 13.6337.8 14.9 28 63.3 36.00 20.48 50 17.7 10.9 43.6 24.4 24.15 14.09 25.112.3 44.1 26.6 27.03 13.07 53 15.6 4.92 32.9 20.3 18.43 11.60 15.1 9.840 23.1 22.00 13.19 57 16.8 2.23 24.8 16.2 15.01 9.38 12 8.69 38.2 18.619.37 13.21 64 13.6 0.5 13.4 12.9 10.10 6.41 5.67 5.24 16 29.6 14.1311.45 71 12.8 0 7.62 12.7 8.28 6.03 3.59 4.32 10.2 25.6 10.93 10.22 789.27 0 4.46 9.05 5.70 4.40 2.6 2.71 6.54 13.8 6.41 5.25 85 6.3 0 2.76.71 3.93 3.18 2.28 2.17 5.2 11.4 5.26 4.33

Table 11 summarizes the PK parameters derived from the PK curves forGroups III and V animals. Standard deviation (SD) and coefficient ofvariation (CV %) are also provided.

TABLE 11 T_(max) C_(max) AUC_((0-t)) AUC_((0-∞)) T_(max-1) C_(max-1)T_(max-2) C_(max-2) d μg/L μg/L*d μg/L*d d μg/L d μg/L Group  #9 30.0029.70 1393.52 1517.94 22.00 28.40 30.00 29.70 III #10 9.00 164.502522.18 2522.83 9.00 164.50 37.00 58.30 #11 9.00 252.00 5364.80 5401.239.00 252.00 36.00 89.90 #12 11.00 108.00 2561.81 2709.05 11.00 108.0039.00 42.90 Mean 14.75 138.55 2960.58 3037.76 12.75 138.23 35.50 55.20SD 10.21 93.68 1691.86 1660.22 6.24 94.18 3.87 25.92 CV % 69.22 67.6157.15 54.65 48.93 68.14 10.91 46.95 Group #17 11.00 224.50 5170.745195.24 11.00 224.50 34.00 172.50 V #18 36.00 41.10 1214.94 1256.9913.00 24.00 36.00 41.10 #19 11.00 70.00 2387.95 2483.33 11.00 70.0036.00 50.70 #20 39.00 111.00 4121.45 4350.73 17.00 105.50 39.00 111.00Mean 24.25 111.65 3223.77 3321.57 13.00 106.00 36.25 93.83 SD 15.3580.51 1763.57 1782.79 2.83 85.76 2.06 60.89 CV % 63.29 72.11 54.71 53.6721.76 80.90 5.69 64.90

Discussions

Based on the animal studies and the in vivo PK data obtained, thefollowing observations are made with regard to the dosing regimens ofthe paliperidone palmitate injectable suspension according to theembodiments disclosed herein.

FIG. 10A shows the average PK curves based on the plasma concentrationdata obtained from animals of Groups I (standard RLD Regimen), Group II(Regimen A) and Group III (Regimen B). As shown, with the heightenedinitial dose of 225 mg human equivalent dose of paliperidone aspaliperidone palmitate, Regimen B reached C_(max) earlier (T_(max)≈14days) than RLD Regimen (T_(max)≈17 days) did, even though the latter hada combined first and second loading of 250 mg (human equivalent dose).Under Regimen B, the C_(max) was comparable to that of RLD Regimendespite having a heightened loading dose, thus alleviating concerns ofadverse effects associated with the plasma concentrations ofpaliperidone being too high. Furthermore, despite the longer intervalbetween the first and second dose under Regimen B, the trough (day 28)was comparable to the plasma concentration on day 28 under RLD Regimenand was indeed higher than the trough under the RLD Regimen (day 35).The overall drug exposures (AUC) are comparable for all three Regimens.

FIG. 10B shows the average PK curves based on plasma concentration dataobtained from animals of Groups IV (RLD Regimen) and Group V (RegimenB). Consistent with the results shown in FIG. 10A, Regimen B reachedC_(max) earlier, despite having only a single loading dose that is lowerthan the combined first and second loading doses of RLD Regimen. UnderRegimen B, despite having a heightened initial loading dose, the C_(max)was comparable to that of RLD Regimen. In addition, under Regimen B, thetrough (day 28) was comparable to the same-day concentration of RLDRegimen and higher than the trough of the RLD Regimen.

The in vivo data based on the animal studies appear consistent with thesimulated data shown in Example 3 (see Table 4).

The various embodiments described above can be combined to providefurther embodiments. All of the U.S. patents, U.S. patent applicationpublications, U.S. patent applications, foreign patents, foreign patentapplications and non-patent publications referred to in thisspecification and/or listed in the Application Data Sheet, including butnot limited to U.S. Provisional Patent Application No. 62/578,082, filedOct. 27, 2017, and U.S. Provisional Patent Application No. 62/647,333,filed Mar. 23, 2018, are incorporated herein by reference in theirentirety. Aspects of the embodiments can be modified, if necessary toemploy concepts of the various patents, applications and publications toprovide yet further embodiments.

These and other changes can be made to the embodiments in light of theabove-detailed description. In general, in the following claims, theterms used should not be construed to limit the claims to the specificembodiments disclosed in the specification and the claims, but should beconstrued to include all possible embodiments along with the full scopeof equivalents to which such claims are entitled. Accordingly, theclaims are not limited by the disclosure.

1. A dosing regimen for administering paliperidone palmitate to apatient in need of treatment of schizophrenia or schizoaffectivedisorders, the dosing regimen comprising: (1) administeringintramuscularly to the patient a first loading dose of 312 mg-468 mgpaliperidone palmitate on the first day of treatment; and (2) beginningon the 29th day ±7 days from the first loading dose, administeringintramuscularly to the patient a first monthly maintenance dose in therange of 39 mg to 234 mg paliperidone palmitate, wherein each dose ofpaliperidone palmitate is formulated in an aqueous suspensionformulation.
 2. The dosing regimen of claim 1 wherein the first loadingdose comprises 351 mg paliperidone palmitate and the first monthlymaintenance dose following the first loading dose comprises 156 mgpaliperidone palmitate.
 3. The dosing regimen of claim 1 furthercomprising, subsequent to the first monthly maintenance dose, one ormore further monthly maintenance doses in the range of 39 mg-234 mgpaliperidone palmitate.
 4. The dosing regimen of claim 3 wherein each ofthe one or more further monthly maintenance doses is 117 mg paliperidonepalmitate.
 5. The dosing regimen of claim 1 wherein the paliperidonepalmitate is in the form of submicron-sized particles having specificsurface areas in the range of 2-15 m²/g.
 6. The dosing regimen of claim1 as a monotherapy.
 7. The dosing regimen of claim 1 as an adjuncttherapy to antidepressant or mood stabilizer.
 8. The dosing regimen ofclaim 1 wherein the aqueous suspension formulation for each dosecomprises: (a) from 3 to 20% (w/w) of the paliperidone palmitate havinga mass median diameter (d(0.5)) in the range of 900 nm-1.2 μm; (b) from0.5 to 3% (w/w) of polysorbate 20; (c) from 0.5 to 4% (w/w) ofpolyethylene glycol 4000; and (d) up to 2% (w/w) preservatives; and (e)water q.s. ad 100%, wherein the formulation has a pH in the range of7-8.5.
 9. The dosing regimen of claim 8 wherein the aqueous suspensioncomposition for each dose comprises, by w/w %, 15.04% of paliperidonepalmitate; 0.48% of citric acid monohydrate; 0.48% disodium hydrogenphosphate anhydrous; 0.24% sodium dihydrogen phosphate monohydrate;0.27% sodium hydroxide; 2.89% polyethylene glycol 4000; 1.16%polysorbate 20; and 79.43% water.
 10. A dosing regimen for administeringpaliperidone palmitate to a patient in need of treatment ofschizophrenia or schizoaffective disorders, the dosing regimencomprising: (1) administering intramuscularly to the patient an initialloading dose of 312 mg-468 mg paliperidone palmitate on the first day oftreatment; and (2) beginning on the 29th day ±7 days from the initialloading dose, administering intramuscularly to the patient a firstmonthly maintenance dose in the range of 39 mg to 234 mg paliperidonepalmitate, wherein each dose of paliperidone palmitate is formulated inan aqueous suspension formulation.
 11. The dosing regimen of claim 10,wherein the initial loading dose comprises 351 mg paliperidone palmitateand the first monthly maintenance dose comprises 156 mg paliperidonepalmitate.
 12. The dosing regimen of claim 10 further comprising,subsequent to the first monthly maintenance dose, one or more furthermonthly maintenance doses in the range of 39 mg-234 mg paliperidonepalmitate.
 13. The dosing regimen of claim 12, wherein each of the oneor more further monthly maintenance doses is 117 mg paliperidonepalmitate.
 14. The dosing regimen of claim 10 wherein the paliperidonepalmitate is in the form of submicron-sized particles having specificsurface areas in the range of 2-15 m²/g.
 15. The dosing regimen of claim10 as a monotherapy.
 16. The dosing regimen of claim 10 as an adjuncttherapy to antidepressant or mood stabilizer.
 17. The dosing regimen ofclaim 10 wherein the aqueous suspension formulation for each dosecomprises: (a) from 3 to 20% (w/w) of the paliperidone palmitate havinga mass median diameter (d(0.5)) in the range of 900 nm-1.2 μm; (b) from0.5 to 3% (w/w) of polysorbate 20; (c) from 0.5 to 4% (w/w) ofpolyethylene glycol 4000; and (d) up to 2% (w/w) preservatives; and (e)water q.s. ad 100%, wherein the formulation has a pH in the range of7-8.5.
 18. The dosing regimen of claim 17 wherein the aqueous suspensioncomposition for each dose comprises, by w/w %, 15.04% of paliperidonepalmitate; 0.48% of citric acid monohydrate; 0.48% disodium hydrogenphosphate anhydrous; 0.24% sodium dihydrogen phosphate monohydrate;0.27% sodium hydroxide; 2.89% polyethylene glycol 4000; 1.16%polysorbate 20; and 79.43% water.
 19. A dosing regimen for administeringpaliperidone palmitate to a patient in need of treatment ofschizophrenia or schizoaffective disorders, the dosing regimencomprising: (1) administering intramuscularly to the patient a firstdose of 312 mg-468 mg paliperidone palmitate on the first day oftreatment; and (2) beginning on the 29th day ±7 days from the firstdose, administering intramuscularly to the patient a second dose in therange of 39 mg to 234 mg paliperidone palmitate, wherein each dose ofpaliperidone palmitate is formulated in an aqueous suspensionformulation.
 20. The dosing regimen of claim 19, wherein the first dosecomprises 351 mg paliperidone palmitate and the second dose comprises156 mg paliperidone palmitate.
 21. The dosing regimen of claim 19comprising, subsequent to the second dose, one or more further monthlymaintenance doses in the range of 39 mg-234 mg paliperidone palmitate.22. The dosing regimen of claim 21, wherein each of the one or morefurther monthly maintenance doses is 117 mg paliperidone palmitate. 23.The dosing regimen of claim 19 wherein the paliperidone palmitate is inthe form of submicron-sized particles having specific surface areas inthe range of 2-15 m²/g.
 24. The dosing regimen of claim 19 as amonotherapy.
 25. The dosing regimen of claim 19 as an adjunct therapy toantidepressant or mood stabilizer.
 26. The dosing regimen of claim 19wherein the aqueous suspension formulation for each dose comprises: (a)from 3 to 20% (w/w) of the paliperidone palmitate having a mass mediandiameter (d(0.5)) in the range of 900 nm-1.2 μm; (b) from 0.5 to 3%(w/w) of polysorbate 20; (c) from 0.5 to 4% (w/w) of polyethylene glycol4000; and (d) up to 2% (w/w) preservatives; and (e) water q.s. ad 100%,wherein the formulation has a pH in the range of 7-8.5.
 27. The dosingregimen of claim 26 wherein the aqueous suspension composition for eachdose comprises, by w/w %, 15.04% of paliperidone palmitate; 0.48% ofcitric acid monohydrate; 0.48% disodium hydrogen phosphate anhydrous;0.24% sodium dihydrogen phosphate monohydrate; 0.27% sodium hydroxide;2.89% polyethylene glycol 4000; 1.16% polysorbate 20; and 79.43% water.